Leukemia inhibitory factor (LIF) belongs to the neuropoietic cytokine family, which also includes ciliary neurotrophic factor (CNTF), oncostatin M (OSM), growth promoting activity, cardiotrophin-1, and interleukin-6 and -11 (IL-6 and IL-11). All of these cytokines are pluripotent, having effects on proliferation and gene expression in a wide variety of cell types in culture. Moreover, all of these cytokines can utilize the same signal transducing receptor subunit, gp130, which exists in a number of different cell types.
LIF has been implicated as having a role in both the neural and immune responses to injury (Patterson PH (1994) Proc Natl Acad Sci USA 91:7833-7835). For example, studies have reported that LIF levels are increased in a variety of animal and human inflammatory conditions (Alexander HR, et al, (1994) Cytokine 6:589-596; Brown et al, (1994) Cytokine 6:300-309; Ulich TR, et al, (1994) Amer Physiol Soc 267:442-446; and Heyman D, et al, (1996) Cytokine 8:410-416).
Within the nervous system, LIF mRNA levels dramatically increase soon after injury (Patterson PH (1994) Proc Natl Acad Sci USA 91:7833-7835; Kurek J B, et al, (1996) Neuromusc Disorders 6:105-114; Banner, L R, et al, (1997) Exper Neurol, in press), and experiments with LIF null mutant (knockout) mice demonstrate that LIF is required for the changes in neuronal gene expression that are characteristic of the injury response (Rao MS, et al, (1993) Neuron 11:1175-1185; Corness J, et al, (1996) Exp Brain Res 112:79-88; and Sun Y, Zigmond RE (1996) Eur J Neurosci 8:2213-2220). Lack of LIF can also lead to premature neuronal death (Sendtner M, et al, (1996) Curr Biol 6:686-694). Moreover, addition of LIF to severed nerves can enhance nerve regeneration and functional recovery (Tham S, et al, (1997) J Neurosci Res 47:208-215).
While these studies implicate LIF as having a role in the nervous and immune systems, there is a need to establish the interactions between the nervous and immune systems during the injury response. Accordingly, it is an object herein to determine the role of LIF in response to or in anticipation of injury, trauma or disorders associated with inflammation and/or pain, and to use LIF to modulate inflammation and pain, individually or together.
It is further an object to use biologically active fragments of LIF and other agonists of the LIF receptor to modulate inflammation and/or pain. It is further an object to administer or upregulate LIF or other agonists of the LIF receptor and particularly the signal transducing receptor subunit gp130, in an individual prior to or simultaneous with activities such as sports, hard labor, or undertaking surgery which generally result in inflammation and pain. It is additionally an object to provide a method of using LIF to prevent and/or reduce the inflammation and/or pain associated with Rheumatoid arthritis.
It is also an object herein to provide methods for screening for modulators of LIF and/or LIF activity, particularly those which enhance the anti-inflammatory activity of LIF.